Lymphatic system regulation of anti-cancer immunity and metastasis

Abstract

Cancer dissemination to lymph nodes (LN) is associated with a worse prognosis, increased incidence of distant metastases and reduced response to therapy. The LN microenvironment puts selective pressure on cancer cells, creating cells that can survive in LN as well as providing survival advantages for distant metastatic spread. Additionally, the presence of cancer cells leads to an immunosuppressive LN microenvironment, favoring the evasion of anti-cancer immune surveillance. However, recent studies have also characterized previously unrecognized roles for tumor-draining lymph nodes (TDLNs) in cancer immunotherapy response, including acting as a reservoir for pre-exhausted CD8+ T cells and stem-like CD8+ T cells. In this review, we will discuss the spread of cancer cells through the lymphatic system, the roles of TDLNs in metastasis and anti-cancer immune responses, and the therapeutic opportunities and challenges in targeting LN metastasis.

Keywords: cancer metastasis; immunotherapy; lymph node metastasis; lymphatic vessels; tumor-draining lymph node (TDLN).

Figure 1

Cancer cell metastasis through the lymphatic system.During cancer progression, cancer-derived cytokines such as VEGF-C, PDGF-BB, IGF1/2, HGF, FGF2, Interleukin 1 (IL1B), and COX-2 promote lymphangiogenesis. Subsequently, lymphangiogenesis accelerates the egress of T cells and suppresses T cell activation via LEC cross-presentation and tolerance. The elevation of VEGF-C drives the expression of CCL21 in LECs, enhancing the chemoinvasion of cancer cells into the lymphatic vasculature. Additionally, chemotactic signals such as CXCR4-CXCL12 and CCR8-CCL1 promote lymphatic metastasis. Lymphangiogenesis increases the transport of cancer cell-derived proteins, exosomes, and metabolites to the TDLN, creating pre-metastatic niches that favor cancer cell invasion. The presence of CD11b+Gr1+ myeloid cells in the tumor-draining collecting lymphatic vessels suppresses lymphatic contraction and reduces tumor-antigen transportation to the lymph nodes.

Figure 2

The remodeling of TDLN microenvironment and cancer cells.The invasion of cancer cells leads to the remodeling of stromal cells in the lymph nodes, and cancer cell growth imposes solid stress, which compresses high endothelial venules (HEVs), preventing T cell ingress. In the lymph nodes, cancer cells also undergo metabolic reprogramming, such as the elevation of oleic acid, to gain resistance against ferroptosis in the bloodstream. The unique microenvironment in the lymph nodes drives cancer cell-intrinsic interferon signaling pathways, causing the elevation of MHC class I and MHC class II in cancer cells. This leads to resistance to NK cell killing and the accumulation of Treg cells in TDLNs through anergic mechanisms.

Figure 3

Tumor-draining lymph node in anti-tumor immune responses. TDLNs are the major site where dendritic cells (DCs) present tumor antigens to T cells. Pre-exhausted CD8+ T cells (Tpex) are enriched in the TDLNs and expand after immune checkpoint blockade (ICB) treatment. For example, in the TDLNs, tumor-specific PD-1+ T cells interact with PD-L1+ DCs. Administering PD-L1 inhibitors to TDLNs enhances anti-tumor T cell immunity and accelerates the infiltration of Tpex CD8+ T cells into the tumor, leading to improved tumor control. The stem-like TCF1+ CD8+ T cells do not form a stable population in the tumor. Instead, they continuously egress to the TDLNs via lymphatic drainage. From the TDLNs, they travel through efferent lymphatics, enter the blood circulation, and then circulate back to the tumor, replenishing the population within the tumor.